Feasibility of Bioengineered Tracheal and Bronchial Reconstruction Using Stented Aortic Matrices

Abstract

Importance: Airway transplantation could be an option for patients with proximal lung tumor or with end-stage tracheobronchial disease. New methods for airway transplantation remain highly controversial.

Objective: To establish the feasibility of airway bioengineering using a technique based on the implantation of stented aortic matrices.

Design, setting, and participants: Uncontrolled single-center cohort study including 20 patients with end-stage tracheal lesions or with proximal lung tumors requiring a pneumonectomy. The study was conducted in Paris, France, from October 2009 through February 2017; final follow-up for all patients occurred on November 2, 2017.

Exposures: Radical resection of the lesions was performed using standard surgical techniques. After resection, airway reconstruction was performed using a human cryopreserved (-80°C) aortic allograft, which was not matched by the ABO and leukocyte antigen systems. To prevent airway collapse, a custom-made stent was inserted into the allograft. In patients with proximal lung tumors, the lung-sparing intervention of bronchial transplantation was used.

Main outcomes and measures: The primary outcome was 90-day mortality. The secondary outcome was 90-day morbidity.

Results: Twenty patients were included in the study (mean age, 54.9 years; age range, 24-79 years; 13 men [65%]). Thirteen patients underwent tracheal (n = 5), bronchial (n = 7), or carinal (n = 1) transplantation. Airway transplantation was not performed in 7 patients for the following reasons: medical contraindication (n = 1), unavoidable pneumonectomy (n = 1), exploratory thoracotomy only (n = 2), and a lobectomy or bilobectomy was possible (n = 3). Among the 20 patients initially included, the overall 90-day mortality rate was 5% (1 patient underwent a carinal transplantation and died). No mortality at 90 days was observed among patients who underwent tracheal or bronchial reconstruction. Among the 13 patients who underwent airway transplantation, major 90-day morbidity events occurred in 4 (30.8%) and included laryngeal edema, acute lung edema, acute respiratory distress syndrome, and atrial fibrillation. There was no adverse event directly related to the surgical technique. Stent removal was performed at a postoperative mean of 18.2 months. At a median follow-up of 3 years 11 months, 10 of the 13 patients (76.9%) were alive. Of these 10 patients, 8 (80%) breathed normally through newly formed airways after stent removal. Regeneration of epithelium and de novo generation of cartilage were observed within aortic matrices from recipient cells.

Conclusions and relevance: In this uncontrolled study, airway bioengineering using stented aortic matrices demonstrated feasibility for complex tracheal and bronchial reconstruction. Further research is needed to assess efficacy and safety.

Trial registration: clinicaltrials.gov Identifier: NCT01331863.

Conflict of interest statement

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Uzunhan reported receiving personal fees from Roche; personal fees and nonfinancial support from Bohringer Ingelheim; and nonfinancial support from Oxyvie. Dr Valeyre reported being a member of advisory boards on idiopathic pulmonary fibrosis treatment that are supported by Roche and Boehringer Ingelheim; receiving personal fees from AstraZeneca and Isis France; and receiving travel support to attend scientific meetings from Roche and Boehringer Ingelheim. Dr Carpentier reported being a cofounder and shareholder of Carmat SA. Dr Vicaut reported receiving grant support from Bristol-Myers Squibb; and personal fees from Bristol-Myers Squibb, Pfizer, Novartis, Pierre Fabre, and Ottobock. No other disclosures were reported.

Figures

Figure 1.. De Novo Generation of Cartilage Within Stented Cryopreserved Aortic Matrices After Surgical Resection of End-Stage Tracheal Lesions or Proximal Lung Tumors

A, Schematic view of airway transplantation using a stented aortic matrix. After resection with adequate surgical margins of end-stage tracheal lesions or proximal lung tumors, the native airway was reconstructed using a cryopreserved aortic allograft. This biological matrix was supported by a stent to prevent airway collapse. The native airway and the aortic graft were anastomosed with continuous absorbable sutures. Both ends of the stent were fixed to the native airway using 4 nonabsorbable sutures (yellow stitches). B, Schematic view of stent removal after airway reconstruction and clinical follow-up. De novo generation of cartilage within the aortic matrix allowed removal of stents 5 to 39 months after transplantation. Top right, patient 20 had complete resection of recurrent thyroid carcinoma with tracheal invasion followed by tracheal transplantation using a cryopreserved aortic allograft. Bronchoscopy at 8 months after tracheal transplantation showed de novo generation of tracheal cartilage (black arrowhead) (Video). The patient was able to breathe and speak normally through newly formed airways at last follow-up after both stent removal at 5 months and tracheostomy tube decannulation at 7 months. Bottom right, patient 2 had end-stage postintubation stenosis that was treated with tracheal transplantation. Chest computed tomographic (CT) scan at last follow-up (7 years 1 month) after stent removal showed a newly formed trachea (yellow arrowhead).

Figure 2.. Schematic Illustrations of the Intervention Performed for Each of the 20 Patients With End-Stage Tracheal Lesions or Proximal Lung Tumors

In patients 12, 15, 16, and 19, dashed lines indicate bronchial sutures. In patients 5, 11, and 18, gray irregular shapes represent unresectable proximal lung tumors.

Figure 3.. Histology and Immunohistochemistry of Biopsy Specimens of Aortic Allografts

A, Superficial graft biopsy specimen from patient 2 obtained 15 months after tracheal transplantation showed regeneration of a mixed respiratory neoepithelium-like structure (black arrowhead) (hematoxylin-eosin-safran stain). B and C, Cryopreserved aortic allograft biopsy specimens from patient 4 obtained 39 months after tracheal transplantation showed type 2 collagen (B) and Sox9 (C) immunoreactivity (brown). The positive labeling of the cryopreserved aortic allograft for these 2 specific collagen markers suggested the presence of cartilage-like cells. Biopsy specimens from nonimplanted cryopreserved aortic allografts were negative for these markers. Immunohistochemistry for collagen type 2 used goat polyclonal anticollagen type 2 with horseradish peroxidase (HRP)-labeled polymer-antigoat antibody detection system (Envision+ Kit, Dako K4011), 3,3′-diaminobenzidine (DAB+) as the chromogen (brown-colored precipitate at the antigen site), and Mayer hematoxylin counterstain. Immunohistochemistry for Sox9 used a rabbit polyclonal anti-Sox9 with HRP-labeled polymer-antirabbit antibody detection system (Envision+ Kit, Dako K4011), DAB+ as the chromogen (brown-colored precipitate at the antigen site), and Mayer hematoxylin counterstain.